It is well established in clinical experience that complications due to infections subsequent to allografting may result in the rejection of the allograft. The transplant patients often acquire microbial infections during their hospitalization or suffer infections attributable to microorganisms already colonizing the patient when admitted to the hospital. Microbial infection is considered to be a major limiting factor to the success of transplantation. This is particularly so because the immunosuppression required to prevent graft rejection greatly limits the success of conventional antimicrobial treatment in overcoming infections in transplant patients [Rolston et al., Hospital Formul. 22, 710 (1987); Glenn et al., Rev. Infec. Dis. 10, 42 (1988); Young, L. S., J. Infec. Dis. 147, 611 (1983); Delgado et al., South Med. J. 73, 627 (1980); Schimpff, S. C., In: Current Concepts in Antibiotic Therapy for Febrile Episodes in Neutropenic Patients, page 7, Eli Lilly and Co., Indianapolis, Ind. (1983)].
One possible way to control microbial infections in transplant recipients would be to use biological response modifiers (immunomodulators) to augment the immune response. This approach has been successfully carried out in animal models of trauma/infection not associated with transplantation, using IFN-.gamma. treatment. Rodents that were subjected to several different models of trauma were immunosuppressed and showed increased mortality when infected with a variety of bacteria. Prophylaxis or therapy of the rodents with murine gamma interferon resulted in enhanced survival in several of the models. [Hershman et al., Microb. Pathogen. 4, 165 (1988); J. Interferon Res. 8, 367 (1988); Clin. Exp. Immunol. 73, 406 (1988); and Infec. Immun. 56, 2412 (1988); Livingston, D. H. & Malangoni, M. A., J. Surg. Res. 45, 37 (1988); copending U.S. Ser. No. 730,017, filed Jul. 12, 1991, which is a continuation of U.S. Ser. No. 265,411 filed Oct. 31, 1988, now abandoned.]
However, there are strong indications against using IFN-.gamma. treatment to control infections in transplant patients.
It is known that cell membrane molecules encoded by genes of the major histocompatibility complex play an essential role in the interaction between cells of the immune system and a transplanted organ [Thorsby, E., Transplant Proc. 17, 29 (1987)]. Specifically, major histocompatibility complex (MHC) molecules of allografted tissue have the capacity to induce strong immune responses by activating T cells of the recipients. MHC class II molecules appear to be particularly strong transplantation antigens [Klempnauer, et al., Transplant Proc. 17, 1987 (1985)]. Since immunomodulation with IFN-.gamma. treatment is known to include enhanced expression of MHC class II antigens [Interferons and the Immune System, Vilcek, J. & DeMaeyer, Eds., Elsevier Scientific Publishers, B. V., Amsterdam (1985)], there is a valid concern about the use of IFN-.gamma. in the treatment of transplant patients. Indeed, IFN-.gamma. (just as interleukin-2 (IL-2)) has been implicated as an important mediator of allograft rejection. IFN-.gamma. and IL-2 receptor antibodies have been shown to prevent allograft rejection in experimental animals [Landolfo et al., Science 220, 176 (1985); Rosenberg et al., J. Immunol. 144, 4648 (1990); Kirkman, R. L. et al., Transplantation 40, 719 (1985)], and several studies have suggested that lymphokine, and in particular IL-2 and IFN-.gamma. production can be correlated with rejection episodes in renal transplant recipients [Yoshimura, N. and Kahan, B. D., Transplantation 40, 661 (1985); Vie, H. et al., Kidney Int. 28, 553 (1985); Claesson, K. et al., Transplantation 38, 32 (1984)]. Woloszczuk et al., J. Clin. Chem. Clin. Biochem. 24, 729-34 (1986) observed increased serum levels of IFN-.gamma. before rejection episodes, either directly related or unrelated to infections, and suggested that this observation would provide an easy and reliable method for monitoring of the immune status of transplant recipients. Systemic interferon administration in renal transplant recipients had been associated with an increased incidence of organ rejections [Kovarik, J. et al., Transplantation 45, 402 (1988)]. This serious adverse effect was concluded to be a contraindication to the use of interferons in the treatment of renal transplant patients [Baron et al., JAMA 266, 1375 (1991)].
Although the extent of involvement of lymphokines in graft rejection, and especially the mechanism by which they are involved are far from clear, and some studies of the rejection phenomena following IFN-.GAMMA. therapy have produced contradictory results [McKenna, R. M. et al., Transplantation 45, 76 (1988); Ijzermans et al., Transplantation 48, 1039 (1989); Rosenberg et al., supra: Kover et al., Transplantation 49, 148 (1990); Kover K. and Moore, W. V. in Transplantation Proceedings 22, 853-85 (1990)], the potential risk of accelerated graft rejection associated with IFN-.gamma. administration has so far restrained physicians from using IFN-.gamma. to treat infections in transplant patients.
The indications against the administration of lymphokines, and specifically IFN-.gamma. to transplant recipients are even more apparent in view of our knowledge about the mechanism of action of cyclosporins and corticosteroids, which are the most commonly used immunosuppressants in transplantation.
The immunosuppressive action of cyclosporins in transplantation has been extensively studied, and is thought to be primarily due to their potent inhibition of lymphokine production by T cells. Cyclosporin A (CsA) has been shown to inhibit the transcription of IFN-.gamma. and IL-2 mRNA in vitro [Kronke, M. et al., Proc. Natl. Acad. Sci. 81, 5214 (1984); Elliot et al., Science 226, 1439 (1984); Granelli-Piperno et al., J. Exp. Med. 163, 922 (1986)]. Several studies have shown a decrease in interleukin-2 (IL-2) and IFN-.gamma. production of renal transplant recipients on cyclosporin A (CsA) treatment. For example, Yoshimura et al., J. Clin. Immunol. (USA) 9, 322-328 (1989) examined the in vivo effect of CsA administered with steroid on the capacity of peripheral blood mononuclear cells (PBMC) from kidney transplant recipients to generate cytokines and their gene expression at mRNA level. They found that combination therapy with CsA and steroid inhibits both IFN-.gamma. and IL-2 gene expression.
A second, important group of immunosuppressants is the group of corticosteroids (glucocorticoids, GCC). It appears that the most important general cellular mechanisms by which they exert immunosuppressive actions may be their effects on the production and action of soluble factors, such as cytokines [Guyre et al., "Glucocorticoids and the immune system: activation of glucocorticoid-receptor complexes in thymus cells; modulation of Fc receptors of phagocytic cells." In: Progress in Research and Clinical Applications of Corticosteroids, Lee, H. J. and Walker, C. A., eds., Heyden & Son, Philadelphia, 14-27 (1981)]. It has also been reported that the production of IFN-.gamma. is blocked by glucocorticoids [Guyre, et al., J. steroid Biochem. 14, 35-39 (1981); Kelso, A. and Munck, A., J. Immun. 133, 784-791 (1984)], while several parameters of monocyte activation by IFN-.gamma. were either unaffected or enhanced [Girard, et al., J. Immun. 138, 3235-3241 (1987)]. A review of the effects of glucocorticoids on the production and actions of immune cytokines is, for example, provided by Guyre et al., J. steroid Biochem. 30, 89-93 (1988).
In summary, although the exact mechanism of the involvement of lymphokines, and specifically IFN-.gamma. in graft rejection is not entirely understood, published results raise serious concerns about the applicability of lymphokine, e.g. IFN-.gamma. therapy to prevent and fight microbial infection in transplant recipients, and appear to suggest that the potential negative effects of exogenous lymphokine administration could far outweigh any benefit resulting from the treatment of microbial infections.